This invention relates to a lyophilization process and the apparatus used for such a process. Moreover, it relates to the construction of a structure within which a freeze dry (lyophilization) process is carried out in a batch method and under precise control necessary for quality required by the pharmaceutical, research and development and related industries.
When process results must be exacting and when process control is important, such as in the chemical and pharmaceutical industry, including the research and development aspects thereof, freeze dry processes have been carried out in small chambers on a batch basis. This allows the operator to more precisely control what occurs to the product or substance being sublimed (freeze dried) than with continuous or spray operations. Typically, a plurality of beakers or containers are held on shelves in a small vacuum chamber.
Weigmann, in U.S. Pat. No. 3,381,746 shows a vapor condensing apparatus having a hollow housing adapted to be excavated to sub-atmospheric pressure. The apparatus includes a tubular refrigerated condenser spaced from the housing and which forms through a connection to the housing a condensating chamber therefor. The condenser construction provides for a counter flow of vapor from a central inlet over the inner surface of a tubular refrigerated condenser unit and then in the opposite direction along the outer surface of the condenser unit to an outlet thereby insuring maximum extraction of the condensibles from the vapor.
Wilkinson, U.S. Pat. No. 3,672,068, shows a method and apparatus for drying materials where the materials to be dried are placed within a container having a plurality of manifold tubes having holes and extending across the chamber formed within the container. The chamber is filled with material to be evacuated so that this material such as grain, cotton, peat or other related material can be dried. The material surrounds the tubes. The chamber is evacuated when a vacuum is created in the manifold tubes.
Sutherland et al, U.S. Pat. No. 3,795,986, show a modular compartment sublimator for freeze drying various materials such as pharmaceuticals. Sutherland et al discusses the major disadvantages of chamber type freeze dryers and their inflexibility and lack of economy when used for subliming pharmaceuticals. Sutherland has stated what has been accepted by the industry, that the use of a single chamber having several shelves does not permit sublimation of diverse materials for products requiring different length drying times. Sutherland further states that the disadvantage of such chamber type freeze dryer pharmaceutical application is that there is an uneven processing of the products to be freeze dried depending upon its location in the single chamber. To overcome this, Sutherland proposes a sublimation chamber having a plurality of small compartments each acting as an independent sublimation chamber. His solution to the uneven processing problem is to provide a modular type design for his chamber.
Silke, U.S. Pat. No. 4,033,048, shows a freeze drying apparatus having a separate condensing chamber connected to an evaporating chamber by means of extraction pipes. The apparatus is intended for use with a liquid which is spray dried within the evacuated evaporation chamber.
Sutherland, U.S. Pat. No. 4,178,697, shows a condensation chamber for freeze drying bulk materials. A cylindrical vacuum evacuated, evaporation chamber, which is intended to be packed with bulk materials, is connected to a single small tubular evacuation duct which extends along the center line and the entire length of the evacuated evaporation chamber. The chamber is surrounded by a plurality of refrigerant coils so that its outer walls are constantly kept cool. The tubular evacuation duct has a principal opening at a first end of the evaporation chamber and four side openings or holes at the opposite end of the chamber. A baffle is utilized to adjust flow to promote a more even evacuation from both ends of the cylindrical chamber. A large centrally located duct opens onto the center of the chamber and is used to carry air into the condensation evacuated evaporation chamber and over the material packed within the chamber in bulk form.
None of the above apparatus are particularly advantageous in freeze drying materials which are typically processed in batch form in small individual quantities held in individual containers or beakers.
The Hull Corporation of Hatboro, Pa. has made commercially available a freeze dry system having an evacuated evaporation chamber and a condensation chamber adjacent thereto and connected through a single large vacuum duct. Contained in the condensation chamber is a plurality of refrigeration coils through which refrigeration fluid is passed.
A temperature controlled heat transfer fluid used to initially freeze the product is circulated through hollow shelves. This heat transfer fluid is then tempered with heat to replace heat loss due to evaporative cooling when the chamber is evacuated and sublimation occurs. A plurality of product containing bottles or trays are placed in single layers on the plurality of temperature controlled shelves. To aid sublimation and increase heat transfer from the heated shelf to the product container via convection, a small amount of an inert gas is allowed to "leak" through the front door, i.e. the product loading door, of the evaporation chamber. This large, single chamber structure has the disadvantages of uneven processing at various locations within the chamber discussed by Sutherland et al, but has advantages over the other above cited art in that the introduction of an inert gas aids in reducing the partial pressure of the evaporation vapor above each beaker held within the evacuated evaporation chamber.
The introduction of carrier gas into the evacuated vacuum evaporation chamber creates a flow over the product which tends to carry off the vapors evaporating from the product and thereby reduce the vapor partial pressure above the product inducing faster sublimation. This process, however, very often comes with mixed results as the volume and therefore the pressure of the carrier gas introduced into the evacuated evaporation chamber is often very hard to control at a constant flow rate and pressure. Moreover, as the most common structure for this freeze dried apparatus has a single large vacuum duct centrally located at the back of the evacuated evaporation chamber and as the carrier gas is introduced at a single point into the chamber, the introduction of the carrier gas very often increases the uneven processing of product depending upon the products location within the single chamber, i.e. on the shelves therein.
The objects of the present invention are intended to improve the process and the structure for carrying out the process for the batch lyophilization of pharmaceutical, laboratory and research and development samples, which samples are held in small quantities in a plurality of beakers or other open containers in a large vacuum evacuated evaporation housing. A further object is to provide an improved distribution of carrier gas flow over each one of the plurality of sample containing beakers. Another object is to achieve improved control of carrier gas pressure and volumetric rate.